The present invention relates to a method for manufacturing placebo tablets or positive control tablets that are identical to tablets that contain active drugs. Clinical studies to determine the effectiveness of new drugs requires that identical tablets be prepared which contain an active drug, no drug (placebo) and/or a control drug. This is done in order to prevent the patients and investigators from knowing who is receiving the drug that is being tested and for this reason the clinical studies are usually referred to as being xe2x80x9cdouble blindxe2x80x9d. This is because neither the investigator nor the patient can tell from the packaging which dosage form is the new drug.
In the prior art when a drug manufacturer carried out a test of a product against a competitor""s patented product, it was not unusual to request that the competitor prepare a blinded supply of the product. This would usually be done if the study protocol and results were shared with the competitor.
In the prior art, blinded samples have been prepared by over encapsulation, coating or debranding. Over encapsulation is a process whereby a dosage form, which is usually a tablet, is placed in a capsule. This procedure requires in some cases the use of an oversize capsule which may be difficult to swallow. This process is time consuming and strict quality controls are required to assure that the capsule and tablet are bioequivalent and are manufactured properly. The gelatin and moisture in the capsules may introduce stability problems. Overcoating of tablets has not been successful for embossed tablets because of the formation of ghost images in the areas where the tablets are embossed. The debranding of printed tablets and capsules is a labor intensive process that may raise the question of stability due to the use of solvents for manually deinking the printed matter on the dosage form.
When compendium products are involved, a generic formulation may have to be prepared which requires a development project where stability and bioequivalence have to be demonstrated.
A further alternative is a mill and fill process where tablets are milled and filled into capsules. This procedure maximally disturbs the original dosage form and questions relative to equivalence uniformity, stability and bioavailability must be resolved.
The applicant has devised a process of coating branded dosage forms which does not compromise the integrity of the branded pharmaceutical dosage form but provides an overcoat that is sufficient to cover all product indicia without interfering with the stability or the releasability of the drug.
The invention also provides a method for coating micro tablets for the purpose of xe2x80x9croundingxe2x80x9d the micro tablets to facilitate the mechanical filling of the micro tablets into capsules; a method of isolating incompatible ingredients in micro tablets and a method of incorporating an additional active ingredient into the micro tablet. As used herein a micro tablet is a tablet which is generally considered to be less than 4 mm in diameter (if round) or less than 4 mm in longest dimension. They are prepared with the same ingredients as traditional tablets and capsules which include lactose, starch, microcrystalline cellulose, disintegrants, flow agents and lubricants.
The invention provides a process for coating a branded pharmaceutical dosage form for the purpose of covering any embossed or printed matter or any colored coating by the application of an amount of coating which is sufficient to obscure any identifying indicia without compromising the stability or releasability of the drug that is contained in the dosage form.
The invention also provides a method of coating a micro tablet to form a rounded tablet which may comprise any or all of the following:
(a) sealing said micro tablet by applying a seal coat to form a sealed micro tablet;
(b) applying to said micro tablet an effective amount of a coating which provides a smooth coating over said micro tablet to provide a smoothly coated micro tablet; and
(c) polishing the tablet to form a polished and moisture resistant pharmaceutical dosage form.
A method of separating incompatible micro tablets is disclosed which may comprise any or all of the following:
(a) sealing the incompatible micro tablet by applying a seal coat to form sealed incompatible micro tablet;
(b) applying to said micro tablet an effective amount of coating which provides a smooth coating over micro tablet to provide a smoothly coated micro tablet; and
(c) polishing the coated micro tablet to form a polished and moisture resistant pharmaceutical dosage form.
In addition, there is disclosed a method of incorporating additional active ingredients into a micro tablet, said method may comprise any or all of the following:
(a) coating an active ingredient onto a micro tablet using a solution or suspension of said active ingredient to form a coated micro tablet;
(b) sealing said micro tablet by applying a seal coat to form a sealed micro tablet;
(c) applying to said sealed micro tablet an effective amount of a coating which provides a smooth coating over said micro tablet to provide a smoothly coated micro tablet; and
(d) polishing the smoothly coated micro tablet of step (c) to form a polished and moisture resistant pharmaceutical dosage form.
Accordingly, it is a primary object of the invention to provide a novel method of obscuring the identifying indicia on a pharmaceutical dosage form.
It is also an object of the invention to provide a method of obscuring the printed matter or indicia on a pharmaceutical dosage form without compromising the stability or bioavailability of the pharmaceutical dosage form.
It is also an object of the invention to provide a cost efficient process for obscuring the embossed or printed matter on a pharmaceutical dosage form.
These and other objects of the invention will become apparent from the present specification.
The invention is primarily intended to be applicable to embossed tablets but may be used for coated/printed tablets or capsules or micro tablets.
The first step in the process of the invention is a sealing step that may be carried in a traditional coating pan or in another coating apparatus that is used in the pharmaceutical arts. A high molecular weight polyethylene glycol (e.g. polyethylene glycol 8000 or similar type material) is melted onto the core tablets in such a manner and amount to provide a seal coat around the tablet and to partially or fully cover and/or fill any depressions or elevations of the indicia. Even though the polymer is water soluble, due to its high molecular weight its rate of solution is slow enough to afford the core tablets moisture protection during the process. The polyethylene glycol may be substituted with any polyethylene glycol which is solid at room temperature (25xc2x0 C.). Other polymers, which offer similar water solubility and a similar degree of moisture protection from the latter coating solutions, may be used. An example of this would be substituted polaxamers that are solid at room temperature. Additionally, agents such as beeswax, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, zein, film forming polymers such as hydroxypropyl cellulose, ethylcellulose and polymeric methacrylates can be dissolved in a suitable solvent and applied to the embossed or printed tablets, and may be used, provided that the coating has no substantial effect on the disintegration/dissolution of the dosage form and that the coated dosage form is physiochemically stable.
Solid polyethylene glycol is preferably applied to the core tablet using a 100% solids concentration and a temperature sufficient to melt the polymer and cause it to spread. A melt application process is preferred because this prevents any solvent or water from attacking the pharmaceutical dosage form during or after the initial sealing process. Generally from 1 to 10% by weight, based on the total weight of the tablets, of the dry polymer is applied to seal the tablets. Higher or lower amounts may also be employed. Since the coating efficiency is about 50%, when 10% of a sealing polymer is applied, the weight gain on the tablet will be approximately 5% based on the total weight of the tablets and the dried coating.
After the dosage form is sealed, a sugar coating may be applied onto the sealed pharmaceutical dosage form by the application of a plurality of coats of a low solids (or the like), sugar coating solution (or the like). The low solids sugar solution (or the like) is preferred to ensure that the coating of any embossed or printed surfaces will result in a smooth coating and may comprise sucrose, lactose, dextrose, sorbitol and the like or mixtures thereof. If desired, colorants or opacifiers may be added to the sugar solution. The low solids solutions may comprise from about 30 to 50% by weight of water.
The dusting powder may comprise an antisticking agent such as talc, starch, kaolin, etc. in combination with a sugar such as lactose or dextrose or the like to be used during the sugar coating process to control sticking and to assist in the formation of a rounded smooth surface on the pharmaceutical dosage form.
A 1:1 mixture of lactose:talc (soluble:insoluble ratio of ingredients) is used to minimize negative dissolution effects that may occur if higher amounts of insoluble agents are used. However, different ratios of soluble and insoluble agents may be used if this is not problematic. The final coats may be applied without the aid of any antisticking agent to provide a final smooth effect on the pharmaceutical dosage form prior to the final application of a polishing solution which may comprise a solution of a polymer such as polyethylene glycol 8000 in water and ethanol to provide a non-sticky, aesthetically pleasing surface on the finished product. Other solids which may be used in the polishing solution include waxes, polaxamers, hydroxypropylcellulose, hydroxycellulose, ethylcellulose or the polymeric methacrylates.